Congestive heart failure (CHF) is one of the leading diagnoses in all hospitalized adults. It is estimated that between 2-3 million adults have CHF in the U.S. with approximately 500,000 new cases diagnosed each year. Currently, approximately 11% of all adults over the age of 65 have CHF. CHF is the most costly disease in managed care with annual expenditures related to CHF exceeding $10 billion. Although available therapies can provide considerable improvement for some patients, morbidity and mortality remain high. With a five-year mortality rate that exceeds many cancers and a two-year mortality rate, which claims the lives of 50% of the patients diagnosed with the disease, CHF is clearly a major health problem.
The therapeutic goal for CHF is to make the cardiac muscle pump more efficiently. This is currently achieved by reducing the work of the heart (ACE inhibitors, vasodilators, diuretics and .beta.-adrenergic blockers) and/or increasing myocardial contractility (digoxin and phosphodiesterase inhibitors). Unfortunately, current inotropic therapy for the failing heart is associated with major limitations: digoxin and the phosphodiesterase inhibitors are associated with life-threatening toxicity and .beta. blockers become less effective inotropic compounds as heart failure progresses. Some of the cellular changes that occur in hear failures are summarized in Table 1.
TABLE 1 ______________________________________ Ca current density cAMP content .dwnarw. .beta.-AR .dwnarw. SR Ca channel .dwnarw. stimulated AC .dwnarw. ______________________________________ AR, .beta. adrenergic receptor; AC, adenylate cyclase; SR Ca channel, sarcoplasmic Ca release channel
One promising approach to inotropic therapy is modulation of cardiac ion channels. As indicated in Table 1, the density of calcium channels does not change in the failing human heart making it a plausible target for inotropic therapy. It is through these channels that calcium (Ca.sup.2+) ions enter the cardiac myocyte to elicit excitation-contraction and pumping of blood out of the ventricles.
The regulation of extracellular calcium plays a crucial role in the treatment of several cardiovascular disorders. The most common agents used to regulate calcium ions are calcium antagonists or calcium channel blockers. In essence, these compounds "slow" the entry of calcium ions into the cell and thereby reduce the force or contractility of cardiac muscle resulting in the lowering of blood pressure. Additionally, these agents find use in the treatment of angina caused by abnormal vasoconstriction of coronary arteries and classical effort associated angina.
A smaller class of agents that regulate calcium ions are calcium agonists or calcium channel enhancers. These compounds promote the movement of calcium ions through the cell wall and therefore increase contractility. Such compounds may be useful in the treatment of disorders of lessened cardiac output such as congestive heart failure. Alternatively, they may be used as tools in the pharmacological study of calcium channels. One problem typically encountered in the use of calcium channel enhancers is their elevating effect on blood pressure. Surprisingly, it has been discovered that while Aplidine is a very effective calcium channel enhancer, it has no effect on blood pressure.